The present invention relates to the discovery that daidzein and its metabolites, o-desmethylangolensin and dihydrodaidzein, are useful for altering the concentration of cholesterol constituents in the blood of a human by increasing the concentration of high-density lipoprotein cholesterol and decreasing the concentration of low density lipoprotein cholesterol. The high and low density lipoprotein cholesterol concentration changes in the blood reduce the risk of athereosclerosis and vascular disease.
Cardiovascular disease is a leading cause of morbidity and mortality, particularly in the United States and in Western European countries. Several causative factors are implicated in the development of cardiovascular disease including hereditary predisposition to the disease, gender, lifestyle factors such as smoking and diet, age, hypertension, and hyperlipidemia, including hypercholesterolemia. Several of these factors, particularly hyperlipidemia and hypercholesteremia, contribute to the development of atherosclerosis, a primary cause of vascular and heart disease.
High blood cholesterol concentration is one of the major risk factors for vascular disease and coronary heart disease in humans. Elevated low density lipoprotein cholesterol (hereafter "LDL-cholesterol") and total cholesterol are directly related to an increased risk of coronary heart disease. Cholesterol and Mortality: 30 Years of Follow-Up from the Framingham Study, Anderson, Castelli, & Levy, JAMA, Vol. 257, pp. 2176-80 (1987).
Although high levels of total cholesterol and LDL-cholesterol are risk factors in developing atherosclerosis and vascular diseases, a deficiency of high density lipoprotein cholesterol (hereafter "HDL-cholesterol") has recently been recognized as a risk factor for developing these conditions. Several clinical trials support a protective role of HDL-cholesterol against atherosclerosis. A study has shown that for every 1-mg/dl increase in HDL-cholesterol in the blood, the risk for coronary vascular disease is decreased by 3% in women. High-density Lipoprotein Cholesterol and Cardiovascular Disease: Four Prospective American Studies, Gordon, Probstfield, and Garrison et al., Circulation, Vol. 79, pp. 8-15 (1989).
Ingestion of vegetable protein materials in place of animal protein in the diet is associated with a lower risk of coronary heart disease, which may reflect decreases in serum cholesterol levels. Vegetable protein materials, particularly soy protein materials, are known to reduce total cholesterol and LDL-cholesterol levels in the blood of animals. A recent meta-analysis of the effects of soy protein intake on serum lipids in humans has shown that dietary soy protein is significantly related to lowering serum concentrations of total cholesterol and LDL-cholesterol in humans without significantly affecting HDL-cholesterol concentrations. Meta-Analysis of the Effects of Soy Protein Intake on Serum Lipids, Anderson, Johnstone, and Cook-Newell, N. Engl. J. Med., Vol. 333, No. 5, pp. 276-82 (1995). Phytoestrogens in the soy protein are recognized as a potentially significant factor in the hypocholesteremic effects of soy protein.
Phytoestrogens, such as those found in soy, are compounds that are structurally similar to estrogen which are derived from plants. Estrogen itself has been determined to be a significant cardioprotective factor. Postnenopausal women taking estrogen replacement therapy have been shown to have a reduced risk of coronary heart disease and myocardial infarction. One mechanism by which estrogen is thought to reduce the risk of coronary heart disease is by inhibiting the development of atherosclerosis through estrogenic reduction of the blood concentration of atherogenic compounds such as LDL cholesterol. Administration of estrogen to estrogen deficient women, however, has been associated with increased risk of developing breast and endometrial cancer, limiting the usefulness of estrogen as a vascular and cardioprotective agent.
Phytoestrogens--particularly the isoflavones derived from soy and clover such as genistein, daidzein, glycitein, their glucosidic derivatives, biochanin A, and formononetin--exhibit estrogenic properties in some mammalian and human tissues, and exhibit anti-estrogenic properties in other tissues by competitively inhibiting estrogen binding at estrogen receptor sites. Unlike estrogen, these isoflavone phytoestrogens are not associated with an increased risk of cancer, and may actually inhibit the development of breast and uterine cancers.
Recent studies have determined that these isoflavones lower blood concentrations of total cholesterol and LDL-cholesterol in animals, and thereby inhibit or slow the development of atherosclerosis. The effect of these isoflavones on blood cholesterol levels in humans has been less clear, as indicated in the meta-analysis, however, it is believed that the isoflavones lower total cholesterol and LDL-cholesterol concentrations in the blood.
Despite the progress in developing compounds and methods for lowering total cholesterol and LDL-cholesterol in the blood of humans, there remains a need to develop further compounds which can safely provide these effects on cholesterol levels in the blood to reduce the risk of developing atherosclerosis and vascular disease. There is a further need to develop compounds and methods of increasing HDL-cholesterol levels in the blood of a human to provide the cardioprotective effects of this cholesterol.